title: The impact of genome-wide supported schizophrenia risk variants in the neurogranin gene on brain structure and function.
abstract: The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two common NRGN risk single nucleotide polymorphisms (SNPs) with functional and structural brain-based intermediate phenotypes for schizophrenia. We obtained structural, functional MRI and genotype data of 92 schizophrenia patients and 114 healthy volunteers from the multisite Mind Clinical Imaging Consortium study. Two schizophrenia-associated NRGN SNPs (rs12807809 and rs12541) were tested for association with working memory-elicited dorsolateral prefrontal cortex (DLPFC) activity and surface-wide cortical thickness. NRGN rs12541 risk allele homozygotes (TT) displayed increased working memory-related activity in several brain regions, including the left DLPFC, left insula, left somatosensory cortex and the cingulate cortex, when compared to non-risk allele carriers. NRGN rs12807809 non-risk allele (C) carriers showed reduced cortical gray matter thickness compared to risk allele homozygotes (TT) in an area comprising the right pericalcarine gyrus, the right cuneus, and the right lingual gyrus. Our study highlights the effects of schizophrenia risk variants in the NRGN gene on functional and structural brain-based intermediate phenotypes for schizophrenia. These results support recent GWAS findings and further implicate NRGN in the pathophysiology of schizophrenia by suggesting that genetic NRGN risk variants contribute to subtle changes in neural functioning and anatomy that can be quantified with neuroimaging methods.
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Walton
authors.forename: Daniel
authors.initials: D
authors.lastname: Geisler
authors.forename: Johanna
authors.initials: J
authors.lastname: Hass
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
authors.forename: Jessica
authors.initials: J
authors.lastname: Turner
authors.forename: Anastasia
authors.initials: A
authors.lastname: Yendiki
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.forename: Beng-Choon
authors.initials: BC
authors.lastname: Ho
authors.forename: Dara S
authors.initials: DS
authors.lastname: Manoach
authors.forename: Randy L
authors.initials: RL
authors.lastname: Gollub
authors.forename: Veit
authors.initials: V
authors.lastname: Roessner
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrlich
mesh_terms: D000328:Adult; D000483:Alleles; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008875:Middle Aged; D051579:Neurogranin / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: C496649:NRGN protein, human; D051579:Neurogranin